Worldwide, there are more than 35 million patients suffering from neurodegenerative diseases leading to dementia or movement disorders. Due to the increasing number of population with age above 65 there is a rising tendency (2050 above 50 million). Neurodegenerative diseases are usually caused by abnormal metabolization of proteins termed amyloidogenic in the central nervous system.
One prototypical representative of such disease-causing proteins is the microtubule-associated protein tau. Diseases associated with abnormal phosphorylation, pathological conformational change, aggregation (i.e. oligomerization, polymerization, and fibrillization) and accumulation in the somatodendritic compartment of the axonal microtubule-associated protein tau are called tauopathies.
Tauopathies are classified into primary and secondary tauopathies. Primary tauopathies include, but are not limited to, Progressive Supranuclear Palsy (PSP), Argyrophillic Grain Disease (AGD), Corticobasal Degeneration (CBD), Pick's Disease (PiD), and some other forms of frontotemporal lobar degenerations (FTLD).
The most frequent secondary tauopathy is Alzheimer's disease (AD). It is the most frequent neurodegenerative disease. It accounts for about 40% of the dementia cases, and about 60-80% of the tauopathies. The neuropathological hallmark of AD is the extracellular aggregation of the protein amyloid beta, which is generally believed to be the primary event leading to a secondary intracellular accumulation of the microtubule-associated protein tau in the central nervous system.
All of these disorders are progressive in nature and lead to severe functional impairments, major individual and social burden, and ultimately death of the affected patient.
For all these diseases, currently available therapeutic options are essentially limited to transient and incomplete symptomatic improvements. There is no approved disease-modifying, neuroprotective medical intervention available, which would allow retarding or ideally stopping the progression of the disorder, based on an intervention at the level of essential disease mechanisms, but there exists a huge clinical demand.
On the other hand, for treating patients with neurodegenerative diseases, different compounds for diverse targets are currently in various phases of clinical development, including clinical testing of tau-based therapeutic strategies in manifold approaches. Previously described approaches aiming at the development of neuroprotective treatment of tauopathies include diverse strategies, such as mitochondrial enhancers (e.g. coenzyme Q10), inhibitors of tau kinases (e.g. tideglusib), inhibitors of O-GlcNAcase, stabilizators of microtubules (e.g. davunetide, epothilone D), antiaggregational compounds (e.g. anle 138b), tau-antibodies. None of those approaches, which made their way into a clinical trial, has shown efficacy in patients so far (Poewe et al. 2015).
A number of companies, amongst them larger ones (like AbbVie, BMS, UCB, Roche), but also smaller biotech companies like Asceneuron (OGA inhibition), TauRx (methylene blue), Déclion Pharmaceuticals (PSP; detoxification), Chronos Therapeutics (AD, PSP), Treventis Corp. (AD, PSP; anti-aggregants), Summit Therapeutics Plc. (OGA inhibition), Proteo Tech (PSP), Selvita (AD, tauopathies; DYRKIA kinase inhibitor) and Sellas Biopharmaceuticals (PSP; GABA-A-BZ1 receptor agonist), but also universities (PSP, CBD, 4R-tauopathies; stabilization of microtubules) have (pre-) clinical programs against tauopathies in the development.
The international patent publication WO 2013/192165 proposed to treat neurodegenerative diseases with compounds selectively activating the apoptotic but not the adaptive arm of the unfolded protein response. Reference is made to Chung et al. 2013 (WO2013/192165). Thus, the method aims to selectively activate the apoptotic arm of the unfolded protein response and subsequent apoptotic cell death, whereas, as shown in the detailed description the method of the present invention inversely is demonstrated to prevent rather than to induce cell death through the activation of PERK. The WO 2013/192165 also mentions PERK to be implicated in the unfolded protein response pathway; however, it does not provide any evidence at all that the referenced compounds are indeed PERK activators, which in contrast is the mode of action focused in the present patent application.
Furthermore, concerning PERK, in the prior art the dominant opinion prevails in that neurodegenerative diseases, if anything, should be treated by inhibition of PERK. Reference is made, for example, to the scientific articles: Axten et al. 2012; Ma et al. 2013; Moreno et al. 2013; Pytel et al. 2014; Scheper et al. 2015.
In the prior art, some authors have proposed to stimulate PERK or to activate signaling cascades downstream of PERK to treat neurodegenerative diseases caused by abnormal metabolization of the protein amyloid-beta or the prion protein. Reference is made, for example, to the scientific articles: Lee do et al. 2010; Stockwell et al. 2012.
One prior work suggested that inhibition of PERK would reduce tauopathy. Reference is made to: van der Harg et al. 2014.
However, no prior work has proposed to activate PERK to treat tauopathies, i.e. neurodegenerative diseases induced by abnormal metabolization of the tau protein.
In summary, today there is no approved medical treatment for neurodegenerative tauopathies based on an intervention at the level of essential disease mechanisms, which would allow retarding or ideally stopping the progression of the disorder. There were only few past attempts to address these limitations. None of these interventions fulfilled the criteria of a disease-modifying, neuroprotective intervention in a clinical trial so far.
The object underlying this intervention is the development of a new rational method to ameliorate symptoms and retard disease progression in tauopathies. Another object of the invention is the development of a new rational method to ameliorate symptoms and retard disease progression in tauopathies for treating and/or preventing tauopathies, i.e. primary and/or secondary tauopathies, especially in a patient population suffering from neurodegenerative diseases and/or neurodegenerative conditions, which are at least partially, preferably predominantly, associated with abnormal phosphorylation, pathological conformational change, aggregation (i.e. oligomerization, polymerization, and fibrillization) and accumulation in the somatodendritic compartment of the axonal microtubule-associated protein tau.
Particularly, the object of the present invention is to overcome the reluctance and prejudice in the prior art and to provide new and efficient therapies for the treatment and/or prophylaxis of neurodegenerative diseases and/or of neurodegenerative pathological conditions in higher mammals, particularly in humans, especially of neurodegenerative diseases and/or of neurodegenerative pathological conditions associated with and/or accompanied by tau aggregation. A particular object of the present invention is to provide new and efficient therapies for the treatment and/or prophylaxis of a tauopathy. A further object of the present invention is to provide compounds and/or agents and compositions for such treatment and/or prophylaxis, and the manufacture of the compounds and/or agents and compositions suitable for the said treatment and/or prophylaxis. In this regard, the object of the present invention relates especially to the use of compounds acting as PERK activator, a prodrug thereof, a derivative thereof and/or a pharmaceutically acceptable salt of any thereof, as a medicament in higher mammals, particularly in humans.